U.S. patent application number 16/938234 was filed with the patent office on 2021-01-28 for dermal patch for transdermal administration of ghrelin pathway blocker.
The applicant listed for this patent is Pedram Hamrah, Reza Mollaaghababa. Invention is credited to Pedram Hamrah, Reza Mollaaghababa.
Application Number | 20210023019 16/938234 |
Document ID | / |
Family ID | 1000005166727 |
Filed Date | 2021-01-28 |
![](/patent/app/20210023019/US20210023019A1-20210128-D00000.png)
![](/patent/app/20210023019/US20210023019A1-20210128-D00001.png)
![](/patent/app/20210023019/US20210023019A1-20210128-D00002.png)
![](/patent/app/20210023019/US20210023019A1-20210128-D00003.png)
![](/patent/app/20210023019/US20210023019A1-20210128-D00004.png)
![](/patent/app/20210023019/US20210023019A1-20210128-D00005.png)
United States Patent
Application |
20210023019 |
Kind Code |
A1 |
Hamrah; Pedram ; et
al. |
January 28, 2021 |
DERMAL PATCH FOR TRANSDERMAL ADMINISTRATION OF GHRELIN PATHWAY
BLOCKER
Abstract
Embodiments of the innovation relate to a dermal patch,
comprising a substrate; a set of projections coupled to the
substrate and configured to be at least partially insertable into
skin, at least a portion of each projection of the set of
projections comprising a biodegradable material; and a ghrelin
blocker material encapsulated in the plurality of projections. The
set of projections are coupled to the substrate via an adhesive
that is configured to be dissolved within the skin after the patch
is applied to the skin for a predetermined time, thus resulting in
separation of the set of projections from the substrate. Once
embedded in the skin, the protrusions can degrade and release the
anti-ghrelin antibody encapsulated therein. The released
anti-ghrelin antibody can find its way into the subject's
circulatory system.
Inventors: |
Hamrah; Pedram; (Wellesley,
MA) ; Mollaaghababa; Reza; (Natick, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hamrah; Pedram
Mollaaghababa; Reza |
Wellesley
Natick |
MA
MA |
US
US |
|
|
Family ID: |
1000005166727 |
Appl. No.: |
16/938234 |
Filed: |
July 24, 2020 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62878824 |
Jul 26, 2019 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 16/26 20130101;
A61K 9/7038 20130101 |
International
Class: |
A61K 9/70 20060101
A61K009/70; C07K 16/26 20060101 C07K016/26 |
Claims
1. A dermal patch, comprising: a substrate; a set of projections
coupled to the substrate and configured to be at least partially
insertable into skin, at least a portion of each projection of the
set of projections comprising a biodegradable material; and a
ghrelin blocker material encapsulated in the plurality of
projections, wherein the set of projections are coupled to the
substrate via an adhesive that is configured to be dissolved within
the skin after the patch is applied to the skin for a predetermined
time, thus resulting in separation of the set of projections from
the substrate.
2. The dermal patch of claim 1, wherein the set of projections
comprises a plurality of micro-needled, at least some of the
plurality of micro-needles are configured to be fully insertable
into skin.
3. The dermal patch of claim 1, wherein the set of projections
comprises: a plurality of shafts extending from a top surface of
the substrate, the shafts being at least partially insertable into
the skin; and a plurality of micro-needles coupled to the substrate
by being attached to the plurality of shafts via the adhesive.
4. The dermal patch of claim 1, wherein the biodegradable material
is configured to degrade in the skin so as to release the ghrelin
blocker material.
5. The dermal patch of claim 1, wherein the ghrelin blocker
material is one of an anti-ghrelin antibody and an anti-ghrelin
antibody fragment.
6. The dermal patch of claim 1, wherein the ghrelin blocker
material is embedded in a pocket comprising a polymeric matrix
different than the biodegradable material.
7. The dermal patch of claim 6, wherein the polymeric matrix is
configured to degrade in the skin to provide extended release of
the ghrelin blocker materials.
8. The dermal patch of claim 1, wherein the ghrelin blocker
material comprises anti-ghrelin immunoglobulin G.
9. The dermal patch of claim 1, wherein the biodegradable material
is configured to degrade in the skin to provide extended release of
the ghrelin blocker materials.
10. The dermal patch of claim 1, wherein a concentration of the
ghrelin blocker material in the biodegradable material of the
micro-needles is in a range in a range of about 0.1% to about 70%
by weight.
11. The dermal patch of claim 1, wherein the biodegradable material
of the plurality of micro-needles comprises any of chitosan,
chitin, silk, caboxymethyl cellulose (CMC), chondroitin, collagen,
and gelatin.
12. The dermal patch of claim 1, wherein the projections are formed
integrally with a remainder of the substrate.
13. The dermal patch of claim 1, wherein at least one projection of
the set of projections comprises a plurality of polymeric particles
encapsulating said ghrelin blocker material.
14. The dermal patch of claim 1, wherein at least one projection of
the set of projections defines a channel in which said polymeric
particles are disposed.
15. The dermal patch of claim 1, wherein the channel extends at
least partially from a tip of said at least one projection into a
body of said projection.
16. The dermal patch of claim 13, wherein said polymeric particles
exhibit different sizes.
17. The dermal patch of claim 13, wherein said polymeric particles
are formed of a plurality of different polymeric materials.
18. The dermal patch of claim 1, wherein at least one of said
projections comprises a plurality of layers formed of different
polymeric materials.
19. The dermal patch of claim 18, wherein said different polymeric
materials exhibit different dissolution rates in the skin.
Description
RELATED APPLICATIONS
[0001] This patent application claims the benefit of U.S.
Provisional Application No. 62/878,824, filed on Jul. 26, 2019,
entitled, "A Dermal Patch for Transdermal Administration of Ghrelin
Pathway Blocker," the contents and teachings of which are hereby
incorporated by reference in their entirety.
FIELD
[0002] The present disclosure is generally directed to a dermal
patch for providing controlled release of a ghrelin blocker into a
subject's circulatory system for modulating the subject's appetite,
and more particularly, to a dermal patch that provides controlled
release of a ghrelin blocker into the subject's circulatory
system.
BACKGROUND
[0003] Ghrelin, also known as the "hunger hormone," is a 28 amino
acid peptide hormone that is produced by ghrelinergic cells in the
gastrointestinal tract but also expressed in kidney, pituitary,
pancreas, lymphocytes and brain. The active form of ghrelin is
octanylated at Ser 3. It functions as a neuropeptide in the central
nervous system to modulate appetite. Ghrelin stimulates gastric
acid secretion and motility. Ghrelin levels significantly increase
during fasting and decrease as a response to food intake. In
addition to regulating appetite, ghrelin also plays a significant
role in regulating energy homeostasis.
[0004] The ghrelin receptor (GHS-R1a) is a G-protein-coupled
receptor that is most highly expressed in the hypothalamus. Outside
the central nervous system, GHS-R1a can be found in the liver, in
skeletal muscle and in the heart. It is well known that activating
the GHS-R1a receptor with ghrelin induces an orexigenic state.
SUMMARY
[0005] Conventional use of ghrelin blockers suffers from a variety
of deficiencies. For example, there have been some efforts in using
vaccination to modulate ghrelin level as a form of obesity
prophylaxis and/or treatment. However, in humans, immunization
against ghrelin has not shown promising results. For example, a
randomized, double-blind and placebo-controlled trial with 87 obese
patients aged 18-55 years with a body mass index between 30 and 35.
The participants received four injections of 300 .mu.g of the
vaccine or placebo at weeks 0, 4, 8, and 16. Despite a high
production of ghrelin autoantibodies in the participants who
received the vaccine, there was no additional weight loss achieved
in comparison to the control group.
[0006] By contrast to conventional ghrelin blocker techniques,
embodiments of the present innovation relate to a dermal patch for
transdermal administration of a ghrelin pathway blocker.
[0007] In one embodiment, a dermal patch is disclosed, which
comprises a support substrate having a plurality of shafts
protruding above a surface thereof, said shafts being at least
partially insertable into the skin when the patch is applied to the
skin. A plurality of micro-needles are coupled to the shafts and
are configured to be fully insertable into the skin, where the
micro-needles include a biodegradable material. A ghrelin blocker,
e.g., an anti-ghrelin antibody or antibody fragment, is
encapsulated in said micro-needles. The micro-needles are attached
to the shafts via an adhesive that is configured to be dissolved
within the skin after the patch is applied to the skin for a
predetermined time, thus resulting in separation of the
micro-needles from the shaft. Once embedded in the skin, the
micro-needles, which are formed of a biodegradable polymeric
material, will degrade and release the ghrelin blocker encapsulated
therein. The released ghrelin blocker can find its way into the
subject's circulatory system.
[0008] The sizes of the micro-needles can be adjusted so as to
modify the release profile of the ghrelin blocker embedded in the
micro-needles into the subject's circulatory system. For example,
an increase in the size of the micro-needles can result in a
concomitant increase in the dissolution time of the micro-needles
and hence the release time of the ghrelin blocker into the
circulatory system.
[0009] As discussed in more detail below, the term "ghrelin
blocker" as used herein refers to any of a small molecule, an
antibody, an antibody fragment, an aptamer, an antibody catalyzer,
or any other molecular species that can interact with the ghrelin
hormone (e.g., acylated ghrelin) and/or one or more of its
precursors, e.g., via binding to the ghrelin hormone, to modulate
the biological function of ghrelin, e.g., to inhibit its normal
interaction with the GHS-R1a receptor, e.g., to reduce its
orexigenic effect. By way of example, a ghrelin blocker can be an
antibody or antibody fragment that exhibits specific binding to
ghrelin, acylated ghrelin or a precursor of ghrelin. The term
"anti-ghrelin antibody fragment" as used herein refers to a
fragment (e.g., Fab fragment) of an anti-ghrelin antibody. By way
of example, the ghrelin precursor can be prepro-ghrelin.
[0010] The biodegradable material of the shafts is configured to
degrade in the skin so as to release the ghrelin blocker materials
into the subject's circulatory system.
[0011] In some embodiments, the biodegradable material can be
poly-lactic acid (PLA), polyglycolic acid (PGA),
poly-lactide-co-glycolide (PLGA), polydioxanone (PDS). Further, in
some embodiments, the adhesive can include, for example,
polyethylene glycol (PEG), polyethylene oxide (PEO),
polyvinylpyrrolidone (PVP), gamma-polyglutamic acid (7-PGA),
gelatin and xanthan gum.
[0012] In some embodiments, the concentration of the ghrelin
blocker materials in the biodegradable material can be, for
example, in a range of about 0.1% to about 70% by weight, e.g., in
a range of about 5% to about 60%, or in a range of about 10% to
about 50%, or in a range of about 20% to about 40%, or in a range
of about 25% to about 35%.
[0013] In some embodiments, the anti-ghrelin antibody can include
anti-ghrelin immunoglobulin G. Anti-ghrelin antibodies suitable for
use in the practice of the embodiments can be made using known
techniques for generating polyclonal and monoclonal antibodies. For
example, as is well known in the art, monoclonal antibodies can be
generated using hybridoma-based technology. Human anti-ghrelin
antibodies suitable for use in the practice of some of the
embodiments are commercially available. For example, a human
anti-ghrelin monoclonal antibody marketed by Abcam under the trade
designation EPR20502 (ab209790) can be employed. As another
example, ghrelin human monoclonal antibody (isotype IgG1) marketed
by Enzo with UniProt ID Q9UBU3 can be used. In another example,
anti-ghrelin antibody marketed by Novus Biologicals can be
employed.
[0014] In some embodiments, an anti-prepro-ghrelin antibody
marketed by Phoenix Pharmaceuticals, Inc. (e.g., Prepro (52-75))
can be employed to inhibit the production of ghrelin from the
ghrelin precursor.
[0015] In other embodiments, a ghrelin blocker material can be a
catalytic antibody that can catalyze hydrolysis of the serine ester
of ghrelin to its inactive des-octanoyl form. By way of example, a
catalytic antibody described in an article entitled "Catalytic
antibody degradation of ghrelin increases whole-body metabolic rate
and reduces refeeding in fasting mice," published in Proc. Natl.
Acad. Sci. USA 2008 Nov. 11; 105(45):17487-17492, which is herein
incorporated by reference can be employed. This article discloses
that monoclonal antibodies were obtained through immunization of
mice with ghrelin phosphonate transition state analog, conjugated
to the immunogenic carrier protein keyhole limpet hemocyanin (KLH),
through a covalent link between the thiol moiety of the transition
state analog and an N-maleimidomethyl cyclohexane-1-carboxylate
cross-linker, resulting in hapten 2. The article explains that the
design of this hapten was based on methodology that is
well-established in the field of catalytic antibodies, in which
phosphonate monoester 2 resembles the transition state of the
hydrolysis reaction of the serine ester of ghrelin to its inactive
des-octanoyl form. As a core antigen structure, the first 5
N-terminal amino acids were selected, partly based on studies that
have evaluated truncated analogs of ghrelin, in which
Ser(octanoyl)-ghrelin (1-5) was shown to be the shortest structural
analog to display activity similar to the native hormone.
[0016] The article further explains that another consideration was
that the antibody combining site can host up to 8 amino acid
residues; as such, the octanoate ester as found in natural ghrelin
was truncated to a smaller 4-carbon chain appendage. In addition,
the hapten with 2 isonipecotic acid (Isn) moieties were extended as
a rigid linker to generate a more focused immune response, and a
cysteine residue was included to enable a high-yield conjugation to
KLH (see above).
[0017] Hapten 2 was synthesized on solid phase and was coupled to
KLH through thioether conjugation chemistry; immunization of BALB/c
mice with the immunoconjugate resulted in a panel of 19 monoclonal
catalytic antibodies (mAbs) for analysis. All mAbs were purified
from ascites, using ion-exchange and protein G affinity
chromatography. A screening of the antibodies for catalytic
hydrolysis of rat ghrelin to its des-octanoyl form with use of
synthetic native rat ghrelin (experimental details are provided in
SI Materials and Methods) indicated that several antibodies could
accelerate the hydrolysis of native rat ghrelin. From this initial
screen 3 mAbs demonstrated turn-over and were evaluated in greater
detail.
[0018] As another example, a ghrelin blocker material can be the
biostable aptamer 1-NOX-B11-2.
[0019] In some embodiments, the shafts can have a height that is
sufficient to allow the shafts to penetrate the skin without
injuring the subject. By way of example, in some embodiments, the
height of the micro-needles can be in a range of about 400 microns
to about 800 microns, e.g., in a range of about 500 microns to
about 700 microns. In some embodiments, the shafts can be
cylindrical with a diameter in a range of about 200 microns to
about 400 microns. In other embodiments, the shafts can have a
polygonal cross-sectional profile with a maximum cross-sectional
dimension in a range of about 200 microns to about 400 microns.
[0020] In some embodiments, the micro-needles can have a conical
shape with a height in a range of about 400 microns to about 800
microns and a base radius in a range of about 200 microns to about
400 microns. In some embodiments, the micro-needles can have a
pyramidal shape with a height in a range of about 400 microns to
about 800 microns and a maximum base dimension in a range of about
200 microns to about 400 microns.
[0021] In some embodiments, the above dermal patch can include an
adhesive border surrounding the substrate that allows attaching the
dermal patch to a subject's skin.
[0022] In a related aspect, a dermal patch is disclosed, which
includes a substrate and a plurality of micro-needles that are
coupled to the substrate, where the micro-needles encapsulate a
ghrelin blocker material. The substrate can be a polymeric
substrate. In some embodiments, the micro-needles can be attached
to the substrate via an adhesive such that when in contact with the
skin the micro-needles can be separated from the substrate and be
embedded within the skin. The micro-needles are formed of a
biodegradable material that is degraded once embedded in the skin
to release the anti-ghrelin antibody encapsulated therein. The
released anti-ghrelin antibody can find its way into the subject's
circulatory system.
[0023] In another aspect, a dermal patch is disclosed, which
includes a substrate having a plurality of micro-needles protruding
above a surface thereof. The micro-needles and the rest of the
substrate are formed as an integrated unit. In some embodiments, a
liner can be attached, e.g., via an adhesive, to a surface of the
substrate opposed to the surface from which the micro-needles
protrude.
[0024] In a related aspect, a dermal patch is disclosed, which
comprises a substrate having a plurality of shafts protruding above
a surface thereof, the shafts being at least partially insertable
into the skin, a plurality of micro-needles coupled to the shafts
and configured to be fully insertable into the skin, the
micro-needles comprising a biodegradable material, and a plurality
of polymeric pockets distributed in the micro-needles, where the
polymeric pockets encapsulate the ghrelin blocker materials. The
micro-needles are attached to the shafts via an adhesive that is
configured to be dissolved within the skin after the patch is
applied to the skin for a predetermined time, thus resulting in
separation of the micro-needles from the shafts.
[0025] In some embodiments, the micro-needles and the plurality of
polymeric pockets are formed of different materials. In other
embodiments, the micro-needles and the plurality of polymeric
pockets are formed of the same material.
[0026] Further understanding of various aspects of the invention
can be obtained by reference to the following detailed description
in conjunction with the attached drawings, which are described
briefly below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] The foregoing and other objects, features and advantages
will be apparent from the following description of particular
embodiments of the innovation, as illustrated in the accompanying
drawings in which like reference characters refer to the same parts
throughout the different views. The drawings are not necessarily to
scale, emphasis instead being placed upon illustrating the
principles of various embodiments of the innovation.
[0028] FIG. 1 schematically depicts a dermal patch according to an
embodiment of the present disclosure.
[0029] FIG. 2 is top schematic view of the dermal patch depicted in
FIG. 1.
[0030] FIG. 3 schematically depicts a dermal patch according to
another embodiment of the present disclosure.
[0031] FIG. 4 schematically depicts a dermal patch according to yet
another embodiment of the present disclosure.
[0032] FIG. 5 schematically depicts a dermal patch according to an
embodiment of the present disclosure.
DETAILED DESCRIPTION
[0033] The following detailed description refers to the
accompanying drawings. The same or similar reference numbers may be
used in the drawings or in the description to refer to the same or
similar parts. Also, similarly named elements may perform similar
functions and may be similarly designed, unless specified
otherwise. Details are set forth to provide an understanding of the
exemplary embodiments. Embodiments, e.g., alternative embodiments,
may be practiced without some of these details. In other instances,
well known techniques, procedures, and components have not been
described in detail to avoid obscuring the described
embodiments.
[0034] The present disclosure is generally related to dermal
patches that can be employed to modulate a subject's appetite. As
discussed in more detail below, in some embodiments, a dermal patch
according to the present teachings can include a bio-degradable
portion in which ghrelin blocker materials are encapsulated. Once
in contact, or embedded in, a biological site such as the skin, the
bio-degradable portion will naturally degrade to release the
ghrelin blocker materials, at least a portion of which can find its
way into the subject's circulatory system. In some embodiments, a
ghrelin blocker material can bind to ghrelin and modulate its
biological activity. For example, it can inhibit its interaction
with the ghrelin receptor, thereby modulating the subject's
appetite.
[0035] In some embodiments, an "antibody" refers to a polypeptide
exhibiting specific binding affinity, e.g., an immunoglobulin chain
or fragment thereof, comprising at least one antibody and antibody
fragment. In some embodiments, an antibody comprises an antigen
binding or functional fragment of a full length antibody, or a full
length immunoglobulin chain. For example, a full-length antibody is
an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is
naturally occurring or formed by normal immunoglobulin gene
fragment recombinatorial processes. In embodiments, an antibody
refers to an immunologically active, antigen-binding portion of an
immunoglobulin molecule, such as an antibody fragment. An antibody
fragment, e.g., functional fragment, comprises a portion of an
antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv),
domain antibody (dAb), or single chain variable fragment (scFv). A
functional antibody fragment binds to the same antigen as that
recognized by the intact (e.g., full-length) antibody.
[0036] In some embodiments, the term "antibody" also encompasses
whole or antigen binding fragments of domain, or single domain,
antibodies, which can also be referred to as "sdAb" or "VHH."
Domain antibodies comprise either V.sub.H or V.sub.L that can act
as stand-alone, antibody fragments. Additionally, domain antibodies
include heavy-chain-only antibodies (HCAbs).
[0037] Antibody molecules can be monospecific (e.g., monovalent or
bivalent), bispecific (e.g., bivalent, trivalent, tetravalent,
pentavalent, or hexavalent), trispecific (e.g., trivalent,
tetravalent, pentavalent, hexavalent), or with higher orders of
specificity (e.g., tetraspecific) and/or higher orders of valency
beyond hexavalency. An antibody molecule can comprise a functional
fragment of a light chain variable region and a functional fragment
of a heavy chain variable region, or heavy and light chains may be
fused together into a single polypeptide.
[0038] In some embodiments, the term "anti-ghrelin antibody" refers
to an antibody or an antibody fragment that can specifically bind
to ghrelin so as to inhibit, or at least reduce, the binding
affinity of ghrelin to a respective ghrelin receptor (Growth
hormone secretagogue receptor (GHS-R). An anti-ghrelin antibody
fragment refers to a Fab region of the anti-ghrelin antibody.
[0039] In some embodiments, the term "micro-needle" refers to a
structure that extends from a proximal end to a sharp distal end,
which is configured for contact with, and/or penetration into, the
skin.
[0040] FIG. 1 schematically depicts a dermal patch 100 according to
an embodiment of the present disclosure. Dermal patch 100 includes
a substrate 102 extending from a bottom surface 102a to a top
surface 102b configured for placement at a biological site such as
the skin. The substrate 102 further includes a set of projections
107 that protrude from the substrate 102.
[0041] In one arrangement, the set of projections 107 include a
plurality of shafts 103 that extend from the tope surface 102b of
the substrate 102 and a plurality of biodegradable pyramidal-shaped
micro-needles 106 that are attached to the top ends of the shafts
103 (for ease of illustration, the shafts 103 are not drawn to
scale). Ghrelin blocker materials 108 are encapsulated within the
micro-needles 106 for transdermal administration to an individual,
as discussed in more detail below. In some embodiments, the ghrelin
blocker materials 108 are embedded in pockets made of a polymeric
matrix that is different from the polymeric matrix forming the
micro-needles 106. In other embodiments, the ghrelin blocker
materials 108 can be directly embedded within the polymeric matrix
forming the micro-needles 106.
[0042] In some embodiments, the substrate 102 can have a
rectangular prism shape with a length (L1) in a range of about 5 mm
to about 20 cm, a height (H) in a range of about 1 mm to about 5
mm, and width (W) (perpendicular to the page and not shown in FIG.
1) in a range of about 5 mm to about 20 cm. It should be understood
that these are merely examples of the shape and its dimensions. In
one arrangement, the substrate 102 may be configured to have a
number of other shapes, such as a prism with a non-rectangular
base, e.g., circular, oval, etc., with other dimensions as suitable
for a particular application.
[0043] Further, in some embodiments, the shafts 103 can have a
cylindrical shape with a height (h) in a range of about 400 microns
to about 900 nm, and a base diameter (d) in a range of about 200
microns to about 400 microns. In some other embodiments, the shafts
103 may be configured to haves a non-cylindrical shape, such as a
prism shape with a cross section that is triangular, pentagonal,
hexagonal, etc.
[0044] Further, the micro-needles 106 can have a length (l) in a
range of about 250 microns to about 800 microns and a base width
(w) in a range of about 200 microns to about 400 microns.
[0045] It should be understood that the substrate 102, the shaft
103, and the micro-needles 106 can have other shapes and dimensions
so long as the patch 100 is capable of delivering the ghrelin
blocker materials 108 to a subject's skin with minimal, if any,
injury.
[0046] The substrate 102 can be formed of any suitable polymeric
material, such as biodegradable polymeric materials. By way of
example, in some embodiments, the substrate 102 can be formed of a
biodegradable polyester polymer and copolymer, such as, polylactic
acid (PLA), polyglycolic acid (PGA), poly-lactide-co-glycolide
(PLGA) and polydioxanone (PDS) or derivatives thereof.
[0047] The micro-needles 106 can also be formed of a variety of
biodegradable materials. By way of example, in some embodiments,
the micro-needles 106 can be formed of biodegradable polymeric
materials, such as chitosan, chitin, silk, carboxymethyl cellulose
(CMC), chondroitin, collagen, and gelatin, among others.
[0048] In one embodiment, the micro-needles 106 can be attached to
the shafts 100 via an adhesive 105 that can allow facile separation
of the micro-needles 106 from the shafts 103 when the micro-needles
106 penetrate the skin. In this manner, the micro-needles 106 can
be embedded in the skin. Such an adhesive 105 can be coated on the
top surfaces of the shafts 103. Placement of the micro-needles 106
onto the adhesive-coated shaft ends provides for connection of the
micro-needles 106 to the shafts 103. Some examples of suitable
adhesives 105 can include, without limitation, polyethylene glycol
(PED), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP),
polyvinyl alcohol (PVA), gamma-polyglutamic acid (.gamma.-PGA),
gelatin, maltose, xanthan gum, among others.
[0049] In some embodiments, the micro-needles 106 can be configured
as pyramidal shapes having relatively sharp tips, which can
facilitate the penetration of the micro-needles 106 into the skin.
For example, during an application procedure, the micro-needles 106
can penetrate the stratum corneum and can be embedded in the
epidermis, where they can naturally degrade to release the ghrelin
blocker materials (e.g., anti-ghrelin antibodies) 108 encapsulated
within the polymeric matrix of the micro-needles 106. In some
embodiments, the penetration depth of the micro-needles 106 can be,
for example, in a range of about 250 microns to about 800
microns.
[0050] It should be understood that the micro-needles 106 can be
configured in a variety of shapes. For example, the micro-needles
106 can be cone-shaped, needle-shaped (e.g., in the shape of
elongated, sharp cylinders), or of any other shape that can
facilitate penetration of the micro-needles 106 into the skin.
[0051] In some embodiments, the concentration of the ghrelin
blocker materials 108 in the micro-needles 106 can be, for example,
in a range of about 1% to about 80%, for example, in a range of
about 10% to about 70%, or in a range of about 20% to about 60%, or
in a range of about 30% to about 50% by weight.
[0052] With additional reference to FIG. 2, the patch 100 can have
a border 200 having a bottom surface to which an adhesive 202 is
applied to facilitate affixation of the patch 100 to a skin
site.
[0053] In use, the patch 100 can be applied to a skin site such
that at least some of the shafts 103 and at least some of the
micro-needles 106 at least partially, and in certain arrangements
fully, penetrate through the skin. In this embodiment, the
micro-needles 106 separate from the respective shafts 103 and
become embedded in the skin, e.g., within the epidermis. Once
embedded in the skin, the polymeric matrix can naturally decompose,
and be absorbed and/or metabolized, thereby releasing the ghrelin
blocker materials 108 encapsulated within the micro-needles
106.
[0054] Without being limited to any particular theory, at least a
portion of the released ghrelin blocker materials 108 can find
their way to the subject's circulatory system. Without being
limited to any particular theory, at least some of the ghrelin
blocker materials 108 can bind to circulating ghrelin. Such binding
of the ghrelin blocker materials 108 to the circulating ghrelin can
modulate biological activity of ghrelin within the subject. By way
of example, the binding of the ghrelin blocker material 108 to
ghrelin can inhibit ghrelin's activation of GHSR1a receptor. For
example, the binding of the ghrelin blocker materials 108 to
ghrelin can inhibit the binding of ghrelin with the GHSR1a
receptor, or reduce the binding affinity of ghrelin with GHSR1a
receptor, thereby modulating the activation of the GHSR1a receptor.
This can in turn modulate, e.g., inhibit, the activation of the
respective orexigenic neural circuits. In some embodiments, such
modulation of the neural circuits can curb a subject's
appetite.
[0055] According to some embodiments, in one method of
manufacturing the dermal patch 100, in an initial step, a
biodegradable polymeric solution is added to 1% of acetic acid
solution to uniformly mix the mixture, and the mixture is then
placed in deionized water for dialysis until achieving a pH value
of about 6. In some embodiments, the mixture can be subsequently
heated to evaporate additional water and achieve a desired
concentration of the polymer, e.g., about 10 to 20 weight percent.
This is followed by adding the anti-ghrelin antibodies 108 to the
mixture and uniformly stirring the mixture. A portion of the
mixture can then be placed on a mold. The mold covered with
anti-ghrelin impregnated mixture can then be placed in a centrifuge
machine and can be centrifuged at a rate, e.g., in a range of about
2000 to about 5000 rpm, at room temperature for a time duration,
e.g., in a range of about 1 to about 2 hours. The mold has cavities
in the shape of a pyramidal or conical micro-needles, which can
receive the drug impregnated polymeric solution. The excess mixture
on the exterior surfaces of the mold cavities can be removed. The
mold can be subjected to further centrifugation to ensure that the
mixture reaches the bottom of the cavities.
[0056] A pressing tool can then be used to further push the mixture
containing the anti-ghrelin antibodies 108 into the cavities of the
mold and additional steps of centrifugation and pressing can be
performed.
[0057] Subsequently, a substrate 102 having shafts 103 coated with
an adhesive 105 can be aligned and joined with the molded mixture,
as disposed within the cavities of the mold. The combination of the
substrate 102 and the mold can be baked, such as at a temperature
of about 37.degree. C., and the mold can be subsequently removed to
provide the dermal patch 100.
[0058] With reference to FIG. 3, in another embodiment, a dermal
patch 400 according to the present disclosure can include a
substrate 402 extending between a bottom surface 402a and a top
surface 402b with a set of projections 407 extending from the top
surface 402b. The set of projections 407 can include a plurality of
shafts 404. Micro-needles 406 can be attached to corresponding
shafts 404 by an adhesive layer 405.
[0059] A plurality of anti-ghrelin antibodies 408 can be
distributed within a polymeric matrix or polymeric material 410
which form the micro-needles 406. For example, in this embodiment,
at least a portion of the anti-ghrelin antibodies 408 are
encapsulated by pockets 408a covered by a polymeric coating 409.
The polymeric coating 409 material is different than the polymeric
material 410 from which the micro-needles 406 are formed. In other
words, in this embodiment, a plurality of polymeric coated pockets
408a are made from a polymeric material 409 that is distinct from
the polymeric material 410 of the micro-needles 406, are loaded
with the ghrelin blocker materials 408 and are distributed within
the polymeric matrix 410 of the micro-needles 406.
[0060] In this embodiment, the polymeric coating 409 of the pockets
408a can degrade over a relatively longer time scale than the time
scale associated with the degradation of the polymeric material 410
of the micro-needles 406. In some embodiments, the polymeric
material 409 of the pockets 408a and/or molecules linked to the
polymeric material 409 can be selected so as to allow masking of
the pockets 408 from the subject's immune system.
[0061] For example, in this embodiment, a plurality of PEG
molecules are coupled to the outer surface of the polymeric coating
409 of the pockets 408a. As discussed in more detail below, the PEG
molecules can extend the circulation time of the pockets 408a
loaded with the ghrelin blocker materials 408.
[0062] By way of example, in some implementations, the
micro-needles 406 can be formed of polymeric materials, such as one
or more of the polymers listed above, such as chitosan, chitin,
silk, carboxymethyl cellulose (CMC), chondroitin, collagen, and
gelatin, among others. Further, in some embodiments, the polymeric
coating 409 of the pockets 408a can be formed of a polymer, such as
polylactic acid (PLA), polyglycolic acid (PGA),
poly-lactide-co-glycolide (PLGA) and polydioxanone (PDS) or
derivatives thereof.
[0063] In use, the patch 400 can be applied to an individual's skin
such that the micro-needles 406 at least partially, and in certain
arrangements completely, penetrate through the skin. The
micro-needles 406 separate from the respective shafts 404 and
become embedded in the skin, e.g., in the epidermis. Once embedded
in the skin, the polymeric matrix 406 can be naturally decomposed,
absorbed or metabolized, thereby releasing the polymeric pockets
408a loaded with the ghrelin blocker materials 408, which find
their way into the subject's circulatory system. The ghrelin
blocker materials-loaded within polymeric pockets 408a can
gradually degrade within the subject and can release their antibody
(or other ghrelin blocker) cargo 408.
[0064] FIG. 4 schematically depicts a dermal patch 500 according to
another embodiment, which includes a substrate 502 having
projections 507 configured as a plurality of micro-needles 504 that
protrude from a top surface 502b thereof. In this embodiment, the
micro-needles 504 and the rest of the substrate 502 are formed as
an integral unit, e.g., via molding. The micro-needles 504 can
incorporate a plurality of ghrelin blocker materials 506 therein.
The substrate 502 is formed of a biodegradable material, such as
those discussed above, such that upon penetration of the
micro-needles 504 into a subject's skin, the micro-needles 504 can
degrade and release the encapsulated anti-ghrelin antibodies (or
other ghrelin blocker materials) 506.
[0065] With continued reference to FIG. 4, in this embodiment, the
substrate 502 is attached to an adhesive-coated liner (not shown)
that facilitates attachment of the dermal patch 500 to a skin site.
In some embodiments, a thickness (T) of the substrate can be, for
example, in a range of about 1 mm to about 5 mm and a height (H) of
the micro-needles 504 can be in a range of about 200 microns to
about 800 microns, although other sizes may also be employed.
[0066] Without being limited to any particular theory, once
released into a subject's circulatory system, the anti-ghrelin
antibodies 506 can couple to ghrelin (e.g., acylated ghrelin)
and/or a ghrelin precursor circulating in the subject's system to
inhibit ghrelin and/or the ghrelin precursor from activating the
ghrelin receptor.
[0067] FIG. 5 schematically depicts another embodiment of a dermal
patch 600 according to the present teachings, which includes a
backing substrate 602 on which a polymeric layer 604 is disposed.
The polymeric layer 604 includes a plurality of projections 607
(e.g., polymeric projections) that are sized and shaped to allow
their insertion into the skin, e.g., in a manner discussed above in
connection with the previous embodiments.
[0068] In this embodiment, the projections 607 include a polymeric
body 608, which can be formed of one or more of the polymers
disclosed herein, and a polymeric coating 610 that at least
partially covers the polymeric body 608 of the projections 607. As
discussed in more detail below, the polymeric coating 610 can
protect the projections 607 as they are inserted into the skin and
can be dissolved when the projections 607 are disposed within the
skin.
[0069] In this embodiment, the projections 607 define a channel
such as a hollow central channel 612 having an outlet 614 that is
covered by a portion 616 of the polymeric coating 610. In this
embodiment, each of the central channels 612 can be loaded with a
composition containing at least one ghrelin blocker (such as an
anti-ghrelin antibody) 618, such as those disclosed herein.
[0070] Upon insertion of the projections 607 into the skin, the
polymeric coating 610 and covering portion 616 are dissolved within
the skin, thereby unblocking the outlets 614 of the channels 612,
which, in turn, results the release of the ghrelin blocker 618 from
the channels 612 and into the tissue at the skin site. As discussed
above, at least a portion of the released ghrelin blocker 618 can
find its way to the individual's circulatory system to modulate
ghrelin activity.
[0071] In this embodiment, the polymeric coating 610 is formed of
PVP (polyvinylpyrrolidone), which is dissolved relatively quickly
once inserted into the skin. In some embodiments, by adjusting a
thickness of the polymeric coating 610, the rate of release of the
ghrelin blocker 618 can be modified. By way of example, in some
embodiments, the polymeric coating 610 can have a thickness in a
range of about 0.5 mm to about 5 mm, e.g., in a range of about 1 mm
to about 2 mm, though other thicknesses can also be used. Such
controlled release of the ghrelin blocker material 618 can be
useful titrating the blood concentration of the ghrelin blocker
material 618.
[0072] In some implementations, the polymeric projections 607 and
the backing substrate 602 are formed as a unitary structure, e.g.,
via injection molding or other suitable techniques. In some such
embodiments, the polymeric projections 607 remain attached to the
backing substrate 602 at least for a substantial portion of the use
of the patch 600 on the skin. In other embodiments, the polymeric
projections 607 can be formed separately from the substrate 602 and
can be attached to the substrate 602, e.g., via an adhesive as
discussed in connection with previous embodiments.
[0073] While in some embodiments, the polymeric projections 607 are
formed of materials that can dissolve within the skin, in other
embodiments, the polymeric projections 607 remain substantially
intact once inserted into the skin. Further, in some embodiments,
the polymeric projections 607 can be formed of different layers 615
of polymeric materials exhibiting different dissolution rates
within the skin. By way of example, a polymeric projection 607 can
include three layers, where the outer layer is formed of PVP
(polyvinylpyrrolidone), a middle layer formed of polyethylene oxide
(PEO), and an inner layer formed of polyvinyl alcohol (PVA).
[0074] In some embodiments, at least a portion (or all of) the
ghrelin blocker 618 can be encapsulated in a plurality of polymeric
particles (not shown), which are then disposed in the central
channels 612 of the polymeric projections 607. Upon release into
the skin, the polymeric particles can degrade and release the
encapsulated ghrelin blocker 618, e.g., an anti-ghrelin antibody.
While in some embodiments, the polymeric particles have
substantially uniform sizes, in other embodiments, the sizes of the
polymeric particles can vary such that some are degraded more
quickly than others, thereby regulating the time release of the
ghrelin blocker 618. The particles carrying the ghrelin blocker 618
can be formed of any suitable polymeric material, such as those
discussed above for forming the microneedles. In some embodiments,
the size of the polymeric particles (e.g., the diameter of the
particles) can vary in a range of about 10 nm to about 10 mm, e.g.,
in a range of 100 nm to about 1 mm. The smaller particles can
dissolve more quickly than the bigger particles and hence discharge
their ghrelin blocker cargo 618 more rapidly. This can provide an
extended time release of the ghrelin blocker 618 in the subject's
circulatory system.
[0075] Further, in some embodiments, the particles carrying the
ghrelin blocker cargo 618 can be formed of a variety of different
polymeric materials that exhibit different dissolution rates within
the skin and/or in the circulatory system. For example, in some
such embodiments, some of the particles can be formed of PVP and
some of the other particles can be formed of polyethylene oxide.
Further, in some embodiment, both of the types of polymeric
materials from which the particles are formed as well as the size
of the particles can be varied to adjust the release time of the
ghrelin into the subject's circulatory system.
[0076] In one example of a method for fabricating a dermal patch
100 according to the present teachings, micromolds can be
fabricated using photolithography and known molding processes, such
as those described in an article titled "Tapered conical polymer
microneedles fabricated using an integrated lens technique for
transdermal drug delivery" by Park J H et al. and published in
Transactions on Biomedical Engineering 2007; 54(5); 903-913, which
is herein incorporated by reference in its entirety. For example, a
female micro-needle master mold can be formed in SU-8 resin by UV
exposure to create micro-needles (e.g., pyramidal or conical). In
some embodiments, the micro-needles 106 can exhibit a taper from
their base to their tip. By way of example, the base and the tip
can have a width of 300 microns and 25 microns, respectively,
though other sizes can also be employed. In some embodiments, the
lengths of the micro-needles 106 can be in a range of about 600
microns to about 800 microns, though any other suitable length can
also be employed.
[0077] A male micro-needle master structure can be formed, e.g., of
polydimethylsiloxane (PDMS). The male master structure can be
coated with a gold layer (e.g., with a thickness of about 100 nm)
to prevent adhesion of a second PDMS layer cured onto the make
master structure to create a female PDMS replicate-mold.
[0078] In some embodiments, the micro-needle matrix can be formed
by ultra-low viscosity carboxymethylcellulose (CMC), bovine serum
albumin (BSV), and amylopectin in deionized water. Water can then
be evaporated, e.g., by heating the mixture to a temperature in a
range of about 60.degree. C. to about 70.degree. C., until a
desired concentration of one or more solutes (e.g., CMC at about 27
wt %) is achieved, thereby forming a viscous hydrogel. One or more
ghrelin blockers can be mixed with the hydrogel and subsequently,
the hydrogel can be placed on a female micro-needle mold and can be
subjected to centrifugation to fill the mold. The micro-needles 106
can then be released from the mold.
[0079] In use, such micro-needles 106 can be inserted into skin and
can be dissolved within the skin to release their cargo of the
ghrelin blocker 108.
[0080] Further details regarding materials and fabrication methods
and materials that can be employed as informed by the present
teachings to fabricate various embodiments of micro-needles
according to the present teachings can be found, e.g., in an
article titled "Dissolving Microneedles for Transdermal Drug
Delivery," by Jeon Woo Lee et al. published in Biomaterials, 2008
May: 29(13): 2113-2124, which is herein incorporated by reference
in its entirety.
[0081] While several exemplary embodiments and features are
described here, modifications, adaptations, and other
implementations may be possible, without departing from the spirit
and scope of the embodiments. Accordingly, unless explicitly stated
otherwise, the descriptions relate to one or more embodiments and
should not be construed to limit the embodiments as a whole. This
is true regardless of whether or not the disclosure states that a
feature is related to "a," "the," "one," "one or more," "some," or
"various" embodiments. Instead, the proper scope of the embodiments
is defined by the appended claims. Further, stating that a feature
may exist indicates that the feature may exist in one or more
embodiments.
[0082] In this disclosure, the terms "include," "comprise,"
"contain," and "have," when used after a set or a system, mean an
open inclusion and do not exclude addition of other,
non-enumerated, members to the set or to the system. Further,
unless stated otherwise or deducted otherwise from the context, the
conjunction "or," if used, is not exclusive, but is instead
inclusive to mean and/or. Moreover, if these terms are used, a
subset of a set may include one or more than one, including all,
members of the set.
[0083] The foregoing description of the embodiments has been
presented for purposes of illustration only. It is not exhaustive
and does not limit the embodiments to the precise form disclosed.
Those skilled in the art will appreciate from the foregoing
description that modifications and variations are possible in light
of the above teachings or may be acquired from practicing the
embodiments. For example, the described steps need not be performed
in the same sequence discussed or with the same degree of
separation. Likewise various steps may be omitted, repeated,
combined, or performed in parallel, as necessary, to achieve the
same or similar objectives. Similarly, the systems described need
not necessarily include all parts described in the embodiments, and
may also include other parts not described in the embodiments.
Accordingly, the embodiments are not limited to the above-described
details, but instead are defined by the appended claims in light of
their full scope of equivalents.
* * * * *